1. Field of the Invention
The present invention relates to 2-acetoxybenzoic acid and more particularly, the present invention relates to therapeutically useful complexes of 2-acetoxybenzoic acid, i.e., 2-acetoxybenzoic acid-nicotinamide or isonicotinamide complexes.
The novel complexes of this invention exhibit analgesic, antipyretic, and antirheumatic therapeutic activity.
The compound, 2-acetoxybenzoic acid, is commonly known as "aspirin" and/or "acetylsalicylic acid", and is one of the most widely used compounds in the treatment of simple pain and inflammation. 2-acetoxybenzoic acid is widely employed as an analgesic, an antipyretic, an anti-inflammatory and an antirheumatic agent, and it is particularly useful in the relief of fever, headache, myalgia, arthralgia and other pains associated with integumental structures. 2-Acetoxybenzoic acid is generally administered for these conditions in the form of a powder, particle, capsule, solution, tablet or other pharmaceutically acceptable dosage form because it is advantageous from the standpoint that chronic use of the compound will not lead to a tolerance or addiction thereof. Moreover, its toxicity is much lower than most compounds possessing similar pharmacologic activity. See, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, by Goodman and Gilman, Fourth Edition, page 316, 1970 (The MacMillan Company, New York, New York). However, 2-acetoxybenzoic acid, as used for these purposes, is well-known by the practicing skilled artisan of the medical arts to exhibit certain unwanted and deliterious side effects. Specifically, it induces occult hemorrhaging in the gastrointestinal tract, which results from contact of the insoluble solid particulate of the compound with the gastrointestinal mucosa. As a result of this insolubilization, particles of 2-acetoxybenzoic acid will adhere to the gastrointestinal mucosa in the form of crystals and such crystals, taken together with the acidic environment of the gastrointestinal lining, will produce microetching thereof, which in turn, leads to gastrointestinal bleeding. See, J. Pharm. Sci., Vol. 58, pgs 1277-1279, 1969; Clin. Pharm. and Therap., Vol. 10, pgs 400-408, 1969; J. Pharm. Sci., Vol. 10, pgs 1511-1513, 1970; British Medical Journal, Vol. 3, pgs 545-547, 1972; Archives of Internal Medicine, Vol. 129, pgs 457-460, 1972; and Clin. Pharm. and Therap., Vol. 14, No. 1, pgs 62-66, 1973.
2. Description of the Prior Art
To date, it is known that gastric bleeding can be diminished if (1) an aqueous solution of 2-acetoxybenzoic acid is administered or (2) a buffered aqueous solution of 2-acetoxybenzoic acid is administered. However, such solutions leave much to be desired in that they are commercially and consumer-wise unacceptable, i.e., water and/or buffered solutions are unacceptable as a suitable pharmaceutical dosage form.
One product on the market, commercially known as "Alka-Seltzer.RTM." is basically an alkaline effervescent 2-acetoxybenzoic acid formulation, which does exhibit satisfactory water solubility and dissolution, insofar as 2-acetoxybenzoic acid is concerned. However, at least three disadvantages are associated with this product. Firstly, the product is contained in a tablet form and must initially be dissolved in water prior to consumption. Secondly, because the product contains a high amount of sodium ion, it is unacceptable for administration to hypertensive patients (those who suffer from high blood pressure), because it has now been medically established that the sodium ion contributes to hypertension. Thirdly, the alkaline nature of the product per se alters the pH of the blood and urine to the alkaline side. Chronic use of this product could thus initiate alkalosis.
Finally, U.S. Pat. No. 3,312,593 discloses an anti-inflammatory composition, which comprises a physical mixture of 2-acetoxybenzoic acid and nicotinic acid; however, this patent is solely concerned with the recognition that these two compounds, in "admixture" can relieve inflammation and edema. In addition, this reference is strictly concerned with an "admixture" of 2-acetoxybenzoic acid and nicotinic acid and does not concern itself with a "complex" thereof. Moreover, nicotinic acid will cause flushing at the extremities.